Blood component measuring device, method for measuring blood component, and bio-sensor

ABSTRACT

Provided is a blood component measuring device or the like that can further suppress the measurement error of a blood component. The device detects an oxidation-reduction current generated by oxidation-reduction when a first voltage is applied to a first electrode pair  21, 22  of a biosensor  1 , and converts the oxidation-reduction current (glucose response value) into a glucose conversion value. The device detects a current generated when a second voltage is applied to a second electrode pair  23, 24  of the biosensor  1 , and converts the detected current (blood cell amount response value) into a blood cell amount conversion value. The glucose response value is measured more than once and the blood cell amount response value is also measured more than once within a predetermined period after the introduction of the blood into the biosensor  1 . A CPU  72  corrects the glucose conversion value measured within the predetermined period based on at least a part of a plurality of glucose conversion values and a plurality of blood cell amount conversion values obtained from the results of measurement.

TECHNICAL FIELD

The present invention relates to a blood component measuring device thatmeasures a component contained in blood, a method for measuring a bloodcomponent, and a biosensor.

BACKGROUND ART

Patent Document 1 discloses a sensor system or the like for determiningthe concentration of an analyte in a sample. In this sensor system,input signals including multiple duty cycles of sequential excitationpulses and relaxations are input to the sample. Thus, one or moresignals output from the sample within 300 ms of the input of anexcitation pulse may be correlated with the analyte concentration of thesample to improve the accuracy and/or precision of the analysis.

PRIOR ART DOCUMENTS Patent Documents

-   Patent Document 1: JP 2011-506964A

DISCLOSURE OF INVENTION Problem to be Solved by the Invention

In the above sensor system, the pulses are input to the sample more thanonce. However, since the analyte concentration of the sample isdetermined by using the output signals themselves, the measurement errorcannot be fully suppressed.

The present invention has been proposed in view of the abovecircumstances, and it is an object of the present invention to provide ablood component measuring device, a method for measuring a bloodcomponent, and a biosensor that can further suppress the measurementerror of a blood component.

Means for Solving Problem

A blood component measuring device of a first aspect of the presentinvention measures a blood component amount with a biosensor in whichblood is introduced, and a blood component contained in the blood isoxidized and reduced by an oxidoreductase. The blood component measuringdevice includes the following: a blood component amount measurementmeans that detects an oxidation-reduction current generated by theoxidation-reduction when a first voltage is applied to a first electrodepair of the biosensor, and that converts the oxidation-reduction currentinto the blood component amount; a blood cell amount measurement meansthat detects a current generated when a second voltage is applied to asecond electrode pair of the biosensor, and that converts the detectedcurrent into a blood cell amount contained in the blood; a measurementcontrol means that controls the blood component amount measurement meansto measure the blood component amount more than once within apredetermined period after the introduction of the blood into thebiosensor, and that also controls the blood cell amount measurementmeans to measure the blood cell amount more than once within thepredetermined period; and a blood component amount correction means thatcorrects the blood component amount measured by the blood componentamount measurement means based on at least a part of a plurality ofblood component amounts measured by the blood component amountmeasurement means and a plurality of blood cell amounts measured by theblood cell amount measurement means under the control of the measurementcontrol means.

A blood component measuring device of a second aspect of the presentinvention is the blood component measuring device of the first aspectand includes a storage means. The storage means stores record dataincluding a plurality of blood component amounts and a plurality ofblood cell amounts that are converted from the respective currentsdetected more than once within the predetermined period for each bloodwith a known blood component amount and a known blood cell amount. Theblood component amount correction means compares (i) the record dataincluding a blood component amount that is closely approximated to anyblood component amount of the plurality of blood component amountsmeasured and the plurality of blood cell amounts measured with (ii)measured data including the plurality of blood component amountsmeasured by the blood component amount measurement means and theplurality of blood cell amounts measured by the blood cell amountmeasurement means. Then, the blood component amount correction meanscorrects the measured blood component amount to the blood componentamount of blood having the record data that is most closely approximatedto the measured data.

A blood component measuring device of a third aspect of the presentinvention is the blood component measuring device of the second aspectand includes a storage means and a temperature detection means. Thestorage means stores record data including a plurality of bloodcomponent amounts and a plurality of blood cell amounts that areconverted from the respective currents detected more than once withinthe predetermined period for each blood with a known blood componentamount and a known blood cell amount and for each ambient temperature.The temperature detection means detects an ambient temperature. Theblood component amount correction means extracts record data with atemperature closer to the ambient temperature detected by thetemperature detection means, and compares the extracted record data withthe measured data including the plurality of blood component amountsmeasured by the blood component amount measurement means and theplurality of blood cell amounts measured by the blood cell amountmeasurement means. Then, the blood component amount correction meanscorrects the measured blood component amount to the blood componentamount of blood having the record data that is most closely approximatedto the measured data.

A blood component measuring device of a fourth aspect of the presentinvention is the blood component measuring device of the second or thirdaspect. The blood component amount correction means compares (i) anycombination of a blood component amount and a blood cell amount in theplurality of blood component amounts and the plurality of blood cellamounts measured under the control of the measurement control means with(ii) the record data including the same combination of a blood componentamount and a blood cell amount in the plurality of blood componentamounts and the plurality of blood cell amounts stored in the storagemeans. Then, the blood component amount correction means corrects themeasured blood component amount to the blood component amount of bloodhaving the most approximate record data.

A blood component measuring device of a fifth aspect of the presentinvention is the blood component measuring device of any one of thefirst to fourth aspects. The measurement control means controls theblood component amount measurement means to measure the blood componentamount in a first period included in a first half of the predeterminedperiod and in a second period included in a second half of thepredetermined period.

A blood component measuring device of a sixth aspect of the presentinvention is the blood component measuring device of the fifth aspect.The measurement control means controls the blood component amountmeasurement means to measure the blood component amount at least in afirst period of the predetermined period during which a change intemperature of the blood introduced into the biosensor is large and in asecond period of the predetermined period during which a change intemperature of the blood introduced into the biosensor is stable.

A blood component measuring device of a seventh aspect of the presentinvention is the blood component measuring device of the fifth or sixthaspect. The measurement control means controls the blood cell amountmeasurement means to measure the blood cell amount at least in the firstperiod and in the second period, during each of which the bloodcomponent amount is measured by the blood component amount measurementmeans.

A blood component measuring device of an eighth aspect of the presentinvention is the blood component measuring device of any one of thefifth to seventh aspects. The record data and the measured data includethe following: a group of the blood component amount measured in thefirst period and the blood cell amount measured in the first period; agroup of the blood component amount measured in the first period and theblood cell amount measured in the second period; a group of the bloodcomponent amount measured in the second period and the blood cell amountmeasured in the first period; and a group of the blood component amountmeasured in the second period and the blood cell amount measured in thesecond period. The blood component amount correction means compares thesame group between the record data and the measured data.

A blood component measuring device of a ninth aspect of the presentinvention is the blood component measuring device of any one of thefirst to eighth aspects. The measurement control means controls theblood component amount measurement means to apply the first voltage tothe first electrode pair within the predetermined period, and to detectan oxidation-reduction current corresponding to the blood componentamount more than once at predetermined timing of measurement of theblood component amount. The measurement control means also controls theblood cell amount measurement means to apply the second voltage to thesecond electrode pair in a predetermined state before, during, or afterthe predetermined timing of the measurement of the blood componentamount, and to detect a current corresponding to the blood cell amount.

A blood component measuring device of a tenth aspect of the presentinvention is the blood component measuring device of the first aspect.The blood component amount correction means performs a multivariateanalysis with the use of at least a part of the plurality of bloodcomponent amounts and the plurality of blood cell amounts to correct theblood component amount measured by the blood component amountmeasurement means.

A method for measuring a blood component of an eleventh aspect of thepresent invention measures a blood component amount with a biosensor inwhich blood is introduced, and a blood component contained in the bloodis oxidized and reduced by an oxidoreductase. The method includes thefollowing steps of (i) detecting an oxidation-reduction currentgenerated by the oxidation-reduction when a first voltage is applied toa first electrode pair of the biosensor, and converting theoxidation-reduction current into the blood component amount; and (ii)detecting a current generated when a second voltage is applied to asecond electrode pair of the biosensor, and converting the detectedcurrent into a blood cell amount contained in the blood. The bloodcomponent amount is measured more than once within a predeterminedperiod after the introduction of the blood into the biosensor, and theblood cell amount is measured more than once within the predeterminedperiod. The measured blood component amount is corrected based on atleast a part of the plurality of blood component amounts measured andthe plurality of blood cell amounts measured.

A method for measuring a blood component of a twelfth aspect of thepresent invention is the method for measuring a blood component of theeleventh aspect. The method includes the following; referring to recorddata including a plurality of blood component amounts and a plurality ofblood cell amounts that are converted from the respective currentsdetected more than once within the predetermined period for each bloodwith a known blood component amount and a known blood cell amount storedin a storage means; comparing (i) the record data including a bloodcomponent amount that is closely approximated to any blood componentamount of the plurality of blood component amounts measured and theplurality of blood cell amounts measured with (ii) measured dataincluding the plurality of blood component amounts measured and theplurality of blood cell amounts measured; and correcting the measuredblood component amount to the blood component amount of blood having therecord data that is most closely approximated to the measured data.

A method for measuring a blood component of a thirteenth aspect of thepresent invention is the method for measuring a blood component of thetwelfth aspect. The method includes the following: referring to recorddata including a plurality of blood component amounts and a plurality ofblood cell amounts that are converted from the respective currentsdetected more than once within the predetermined period for each bloodwith a known blood component amount and a known blood cell amount andfor each ambient temperature stored in a storage means; detecting anambient temperature; extracting record data with a temperature closer tothe detected ambient temperature, and comparing the extracted recorddata with measured data including the plurality of blood componentamounts measured and the plurality of blood cell amounts measured; andcorrecting the measured blood component amount to the blood componentamount of blood having the record data that is most closely approximatedto the measured data.

A method for measuring a blood component of a fourteenth aspect of thepresent invention is the method for measuring a blood component of thetwelfth or thirteenth aspect. The method includes the following:comparing (i) any combination of a blood component amount and a bloodcell amount in the plurality of blood component amounts measured and theplurality of blood cell amounts measured with (ii) the record dataincluding the same combination of a blood component amount and a bloodcell amount in the plurality of blood component amounts and theplurality of blood cell amounts stored in the storage means; andcorrecting the measured blood component amount to the blood componentamount of blood having the most approximate record data.

A method for measuring a blood component of a fifteenth aspect of thepresent invention is the method for measuring a blood component of anyone of the eleventh to fourteenth aspects. The method includes measuringthe blood component amount in a first period included in a first half ofthe predetermined period and in a second period included in a secondhalf of the predetermined period.

A method for measuring a blood component of a sixteenth aspect of thepresent invention is the method for measuring a blood component of thefifteenth aspect. The method includes measuring the blood componentamount at least in a first period of the predetermined period duringwhich a change in temperature of the blood introduced into the biosensoris large and in a second period of the predetermined period during whicha change in temperature of the blood introduced into the biosensor isstable.

A method for measuring a blood component of a seventeenth aspect of thepresent invention is the method for measuring a blood component of thefifteenth or sixteenth aspect. The method includes measuring the bloodcell amount at least in the first period and in the second period.

A method for measuring a blood component of an eighteenth aspect of thepresent invention is the method for measuring a blood component of anyone of the fifteenth to seventeenth aspects. The record data and themeasured data include a group of the blood component amount measured inthe first period and the blood cell amount measured in the first period,a group of the blood component amount measured in the first period andthe blood cell amount measured in the second period, a group of theblood component amount measured in the second period and the blood cellamount measured in the first period, and a group of the blood componentamount measured in the second period and the blood cell amount measuredin the second period. The blood component amount is corrected bycomparing the same group between the record data and the measured data.

A method for measuring a blood component of a nineteenth aspect is themethod for measuring a blood component of any one of the eleventh toeighteenth aspects. The method includes the following: applying thefirst voltage to the first electrode pair within the predeterminedperiod, and detecting an oxidation-reduction current corresponding tothe blood component amount more than once at predetermined timing ofmeasurement of the blood component amount; and applying the secondvoltage in pulses to the second electrode pair within a predeterminedshort time before, during, or after the predetermined timing of themeasurement of the blood cell amount and only at timing of measurementof the blood component amount in the predetermined period, and detectinga current corresponding to the blood cell amount.

A method for measuring a blood component of a twentieth aspect of thepresent invention is the method for measuring a blood component of theeleventh aspect. The method includes performing a multivariate analysiswith the use of at least a part of the plurality of blood componentamounts and the plurality of blood cell amounts to correct the bloodcomponent amount measured within the predetermined period.

A biosensor of a twenty-first aspect of the present invention is abiosensor in which blood is introduced, and a blood component containedin the blood is oxidized and reduced by an oxidoreductase. The biosensorincludes the following: a blood component amount measuring electrodepair including a working electrode and a counter electrode that are incontact with the oxidoreductase and a mediator; a blood cell amountmeasuring electrode pair including a working electrode that is not incontact with the oxidoreductase and a mediator, and a counter electrodethat is in contact with the oxidoreductase and a mediator, but not incontact with the working electrode of the blood component amountmeasuring electrode pair; and a non-interacting portion that separatesthe working electrode of the blood component amount measuring electrodepair from the counter electrode of the blood cell amount measuringelectrode pair. A first voltage is applied to the blood component amountmeasuring electrode pair to measure a blood component amount of theblood that has been introduced into the working electrode and thecounter electrode of the blood component amount measuring electrodepair, and a second voltage is applied in pulses to the blood cell amountmeasuring electrode pair to measure a blood cell amount contained in theblood that has been introduced into the counter electrode of the bloodcell amount measuring electrode pair.

A biosensor of a twenty-second aspect of the present invention is abiosensor in which in which blood is introduced, and a blood componentcontained in the blood is oxidized and reduced by an oxidoreductase. Thebiosensor includes the following: a blood component amount measuringelectrode pair including a working electrode and a counter electrodethat are in contact with the oxidoreductase and a mediator; a blood cellamount measuring electrode pair including a working electrode that isnot in contact with the oxidoreductase and a mediator, and a counterelectrode that is in contact with the oxidoreductase and a mediator, butnot in contact with the working electrode of the blood component amountmeasuring electrode pair; and a non-interacting portion that separatesthe working electrode of the blood component amount measuring electrodepair from the counter electrode of the blood cell amount measuringelectrode pair.

Effects of the Invention

In the present invention, since the measured blood component amount iscorrected by using the conversion values of a plurality of bloodcomponent amounts and the conversion values of a plurality of blood cellamounts, the measurement error of the blood component can be suppressedcompared to the correction of the blood component amount by using theresponse values themselves.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is an exploded perspective view of a biosensor according to anembodiment of the present invention.

FIG. 2 is a cross-sectional view of a biosensor according to anembodiment of the present invention.

FIG. 3 is a top view of a blood component measurement layer of abiosensor according to an embodiment of the present invention.

FIG. 4 is a block diagram showing a configuration of a measuring deviceaccording to an embodiment of the present invention.

FIG. 5 is a diagram showing the glucose response value and the bloodcell amount response value with respect to a known glucose concentrationand a known blood cell amount.

FIG. 6 is a diagram showing the relationship between the glucoseresponse value and the blood cell amount response value.

FIG. 7 shows an operation of a measuring device to apply a voltage to abiosensor according to an embodiment of the present invention. FIG. 7Ais a diagram showing a change in voltage for obtaining the glucoseresponse value. FIG. 7B is a diagram showing a change in voltage forobtaining the blood cell amount response value.

FIG. 8 is a diagram showing the timing of the measurement of the glucoseresponse value and the blood cell amount response value by a measuringdevice according to an embodiment of the present invention.

FIG. 9 is a diagram showing a glucose concentration conversion matrixcalculated by a measuring device according to an embodiment of thepresent invention.

FIG. 10 is a diagram showing another glucose concentration conversionmatrix calculated by a measuring device according to an embodiment ofthe present invention.

FIG. 11 is a diagram showing another glucose concentration conversionmatrix calculated by a measuring device according to an embodiment ofthe present invention.

FIG. 12 is a diagram showing another glucose concentration conversionmatrix calculated by a measuring device according to an embodiment ofthe present invention.

FIG. 13 is a diagram showing a change in temperature after a sample isintroduced into a biosensor according to an embodiment of the presentinvention.

FIG. 14 is a diagram showing the relationship between the ambienttemperature, the sample introduction temperature, and the glucoseconversion value in a measuring device according to an embodiment of thepresent invention.

FIG. 15 is a diagram showing the relationship between the glucoseresponse value, the blood cell amount response value, and the glucoseconversion value at each temperature of a measuring device according toan embodiment of the present invention.

FIG. 16 is a diagram showing the degree of the influence of the glucoseconversion value on the blood cell amount conversion value in ameasuring device according to an embodiment of the present invention.

FIG. 17 is a diagram showing the relationship between the known glucoseconcentration, the known blood cell amount, the degree of the influenceof temperature, the glucose response value, and the blood cell amountresponse value when the temperature is changed in a measuring deviceaccording to an embodiment of the present invention.

FIG. 18 is a diagram showing the relationship between the glucoseresponse value and the blood cell amount response value when they areaffected by the temperature in a measuring device according to anembodiment of the present invention.

FIGS. 19A & 19B show another operation of a measuring device to apply avoltage to a biosensor according to an embodiment of the presentinvention. FIG. 19A is a diagram showing a change in voltage forobtaining the glucose response value. FIG. 19B is a diagram showing achange in voltage for obtaining the blood cell amount response value.

FIG. 20 is a diagram showing timing of the measurement of the glucoseresponse value and the blood cell amount response value by a measuringdevice according to an embodiment of the present invention.

FIG. 21 is a diagram showing the relationship between a measurementpoint of the glucose response value and the glucose conversion value ina measuring device according to an embodiment of the present invention.

FIG. 22 is a block diagram showing another configuration of a measuringdevice according to an embodiment of the present invention.

DESCRIPTION OF THE INVENTION

Hereinafter, embodiments of the present invention will be described withreference to the drawings.

First, a biosensor 1 will be described.

The biosensor 1 according to an embodiment of the present inventionincludes portions as shown in, e.g., FIGS. 1 to 3. FIG. 1 is an explodedperspective view of the biosensor 1. FIG. 2 is a cross-sectional view ofthe biosensor 1. The biosensor 1 includes a blood component measurementlayer 2, a reagent layer 3, a spacer layer 4, and a surface layer 5.These layers are laminated to form the biosensor 1. In the following,the biosensor 1 will be described as a biosensor for measuring glucoseas a blood cell component, but is not limited thereto.

The biosensor 1 is removably attached to a measuring device 6, whichwill be described later. The biosensor 1 and the measuring device 6constitute a biosensor system. In the biosensor system, a drop of blood(sample) is placed on a sample placement portion 41 that is located onthe front end of the biosensor 1, and the amount of a component of asubstrate contained in the blood (sample) is measured by the measuringdevice 6. As a result of the measurement, the measuring device 6displays the measured blood component amount.

When the biosensor 1 is used to quantify the blood component amount inblood, first, a user inserts an end portion 27 of the biosensor 1 intothe measuring device 6. Then, the measuring device 6 applies a voltageto electrodes of the biosensor 1, as will be described later. In thisstate, blood is supplied to the sample placement portion 41.Subsequently, a drop of blood is placed and drawn into the biosensor 1.The reagent layer 3 is dissolved with this blood. The measuring device 6detects an electrical change that occurs between the electrodes of thebiosensor 1, and measures the blood component amount.

In this embodiment, the biosensor 1 measures a specific blood componentamount contained in human blood (sample liquid). The specific bloodcomponent amount includes a glucose concentration. The followingexplanation relates to the measurement of the glucose concentration inhuman blood. However, the biosensor system of this embodiment can alsomeasure lactic acid, cholesterol, and any other components by selectingappropriate enzymes.

The blood component measurement layer 2 includes an insulating substrate20 and a conductive layer formed on the insulating substrate 20. Theinsulating substrate 20 is made of, e.g., polyethylene terephthalate(PET), polycarbonate (PC), polyimide (PI), polyethylene (PE),polypropylene (PP), polystyrene (PS), polyvinyl chloride (PVC),polyoxymethylene (POM), monomer-cast nylon (MC), polybutyleneterephthalate (PBT), methacrylate resin (PMMA), ABS resin (ABS), orglass. The conductive layer is made of, e.g., noble metals such as gold,platinum, and palladium or electrically conductive materials such ascarbon. The conductive layer is formed by, e.g., screen printing orsputtering. The conductive layer may be provided on the entire surfaceor at least a part of the surface of the substrate. The conductive layermay be coated with a polymeric material in order to prevent adhesion ofimpurities, oxidation, or the like. The coating on the surface of theconductive layer can be performed, e.g., by preparing a solution of thepolymeric material, dropping or applying the solution to the surface ofthe conductive layer, and drying the solution. The drying process is,e.g., natural drying, air drying, hot air drying, or drying by heating.

The size of the insulating substrate 20 is not particularly limited. Forexample, the insulating substrate 20 has a total length of 5 to 100 mm,a width of 2 to 50 mm, and a thickness of 0.05 to 2 mm, preferably has atotal length of 7 to 50 mm, a width of 3 to 20 mm, and a thickness of0.1 to 1 mm, and more preferably has a total length of 10 to 30 mm, awidth of 3 to 10 mm, and a thickness of 0.1 to 0.6 mm.

The material of the spacer layer 4 is not particularly limited and maybe, e.g., the same as that of the substrate 20. The size of the spacerlayer 4 is not particularly limited. For example, the spacer layer 4 hasa total length of 5 to 100 mm, a width of 2 to 50 mm, and a thickness of0.01 to 1 mm, preferably has a total length of 7 to 50 mm, a width of 3to 20 mm, and a thickness of 0.05 to 0.5 mm, and more preferably has atotal length of 10 to 30 mm, a width of 3 to 10 mm, and a thickness of0.05 to 0.25 mm. The spacer layer 4 has an I-shaped notch that serves asthe sample placement portion 41 for the introduction of blood.

The surface layer 5 is an insulating substrate having an air hole 51 inthe center. The surface layer 5 is integrally disposed with the bloodcomponent measurement layer 2 so that the spacer layer 4 having thesample placement portion 41 (notch) is sandwiched between the surfacelayer 5 and the blood component measurement layer 2. In order tointegrally dispose the layers, the surface layer 5, the spacer layer 4,and the blood component measurement layer 2 may be joined using anadhesive or thermally fused together. Examples of the adhesive includean epoxy adhesive, an acrylic adhesive, a polyurethane adhesive, athermosetting adhesive (such as a hot-melt adhesive), and a UV curableadhesive.

The material of the surface layer 5 is not particularly limited and maybe, e.g., the same as that of the substrate 20. It is more preferablethat a portion of the surface layer 4 that corresponds to the ceiling ofthe sample placement portion 41 is subjected to a hydrophilic treatment.The hydrophilic treatment may be, e.g., a method for applying a surfaceactive agent to the surface of the surface layer 5 or a method forintroducing a hydrophilic functional group such as a hydroxyl group, acarbonyl group, or a carboxyl group into the surface of the surfacelayer 5 by plasma processing. The size of the surface layer 5 is notparticularly limited. For example, the surface layer 5 has a totallength of 5 to 100 mm, a width of 3 to 50 mm, and a thickness of 0.01 to0.5 mm, preferably has a total length of 10 to 50 mm, a width of 3 to 20mm, and a thickness of 0.05 to 0.25 mm, and more preferably has a totallength of 15 to 30 mm, a width of 5 to 10 mm, and a thickness of 0.05 to0.1 mm. The cover 12 preferably has the air hole 15, e.g., in the formof a circle, an ellipse, or a polygon. The air hole 51 has, e.g., amaximum diameter of 0.01 to 10 mm, preferably a maximum diameter of 0.05to 5 mm, and more preferably a maximum diameter of 0.1 to 2 mm.

As shown in FIG. 3, a plurality of slits are provided in the conductivelayer on the substrate 20, thereby forming various electrodes of theblood component measurement layer 2. FIG. 3 is a top view of the bloodcomponent measurement layer 2 of the biosensor 1. The blood componentmeasurement layer 2 includes a glucose working electrode 21 and aglucose counter electrode 22 to measure the glucose concentration. Theglucose working electrode 21 and the glucose counter electrode 22 arelocated at the positions where they are in contact with anoxidoreductase and a mediator of the reagent layer 3, as will bedescribed later. The blood component measurement layer 2 includes ablood cell amount working electrode 23 and a blood cell amount counterelectrode 24 to measure the blood cell amount. The blood cell valueworking electrode 23 is located at the position where it is not incontact with the oxidoreductase and the mediator of the reagent layer 3,as will be described later. The blood cell amount counter electrode 24is located at the position where it is in contact with theoxidoreductase and the mediator of the reagent layer 3, as will bedescribed later, but not in contact with the glucose working electrode21. Moreover, the blood component measurement layer 2 includes adetecting electrode 26 to detect the introduction of blood. The glucoseworking electrode 21, the glucose counter electrode 22, the blood cellamount working electrode 23, the blood cell amount counter electrode 24,and the detecting electrode 26 are electrically connected to themeasuring device 6 while the biosensor 1 is being inserted into themeasuring device 6.

To measure the glucose concentration, a voltage (first voltage) isapplied between the glucose working electrode 21 as a positive electrodeand the glucose counter electrode 22 as a negative electrode. Theglucose working electrode 21 and the glucose counter electrode 22function as a blood component amount measuring electrode pair. Tomeasure the blood cell amount, a voltage (second voltage) is applied inpulses between the blood cell amount working electrode 23 as a positiveelectrode and the blood cell amount counter electrode 24 as a negativeelectrode. The blood cell amount working electrode 23 and the blood cellamount counter electrode 24 function as a blood cell amount measuringelectrode pair. The pulses may be in the form of a rectangular wave or atriangular wave. The details of the application of these voltages willbe described later.

A non-interacting portion 25 in which the conductive layer is not formedis provided between the glucose working electrode 21 and the blood cellamount counter electrode 24. The non-interacting portion 25 separatesthe glucose working electrode 21 from the blood cell amount counterelectrode 24. Thus, the non-interacting portion 25 prevents the mediatorgenerated in the blood cell amount counter electrode 24 from flowinginto the glucose working electrode 21 during the measurement of theblood cell amount.

In the blood component measurement layer 2, an identification portionmay be formed by the electrode in order for the measuring device 6 toidentify the biosensor 1. The identification portion may have a shape,e.g., for identifying the type of the biosensor 1 or the difference inthe output characteristics of the production lots. The identificationportion is formed, e.g., on the end portion 27 side of the biosensor 1and can be read by the measuring device 6.

As shown in FIG. 1, the spacer layer 4 is disposed to cover each of theelectrodes 21 to 24, 26 on the substrate 20 of the blood componentmeasurement layer 2. The spacer layer 4 is a substrate 42 having therectangular sample placement portion 41 provided in the center of thefront end. The sample placement portion 41 forms a sample supply path 10shown in FIG. 3. When a drop of blood is placed on the sample placementportion 41, the blood is drawn in the right direction of FIGS. 1 to 3toward the air hole 51 of the surface layer 5 by a capillary action.Consequently, the blood is introduced into the glucose working electrode21, the glucose counter electrode 22, the blood cell amount workingelectrode 23, and the blood cell amount counter electrode 24.

As shown in FIG. 1, the reagent layer 3 is arranged between the bloodcomponent measurement layer 2 and the spacer layer 4. The reagent layer3 is formed by the application of a reagent containing, e.g., an enzyme,a mediator (electron receptor), an amino acid, and sugar alcohol. Thereagent layer 3 is in contact with the glucose working electrode 21 andthe glucose counter electrode 22 that are exposed from the sampleplacement portion 41 of the spacer layer 4. The reagent layer 3selectively includes a polymeric material, an enzyme stabilizer, and acrystal homogenizing agent as optional components. The surface layer 5is disposed on the blood component measurement layer 2 and the reagentlayer 3 via the spacer layer 4, while leaving one end of the bloodcomponent measurement layer 2 uncovered.

Examples of the oxidoreductase of the reagent layer 3 include thefollowing: glucose oxidase; lactate oxidase; cholesterol oxidase;cholesterol esterase; uricase; ascorbate oxidase; bilirubin oxidase;glucose dehydrogenase; lactate dehydrogenase; and lactate dehydrogenase.The amount of the oxidoreductase is, e.g., 0.01 to 100 U, preferably0.05 to 10 U, and more preferably 0.1 to 5 U per one biosensor or onemeasurement. In particular, glucose oxidase and glucose dehydrogenaseare preferred as the oxidoreductase.

The mediator (electron receptor) of the reagent layer 3 is preferablyferricyanide, and more preferably potassium ferricyanide. In addition tothe ferricyanide, the other mediators may include, e.g., p-benzoquinoneand its derivative, phenazine methosulfate, methylene blue, andferrocene and its derivative. The amount of the electron carrier mixedis not particularly limited and may be, e.g., 0.1 to 1000 mM, preferably1 to 500 mM, and more preferably 10 to 200 mM per one measurement or onebiosensor.

To measure, e.g., the glucose concentration (blood component) in humanblood, the biosensor 1 of this embodiment uses glucose oxidase as theoxidoreductase and potassium ferricyanide as the mediator, which arecarried by the reagent layer 3.

When blood is introduced into the sample supply path 10, theoxidoreductase and the mediator of the reagent layer 3 are dissolved inthe blood (sample liquid). Then, an enzyme reaction with glucose (i.e.,the substrate) in the blood proceeds, and the mediator is reduced toform ferrocyanide (potassium ferrocyanide in this embodiment). After thecompletion of this reaction, the reduced mediator is oxidizedelectrochemically, and the resultant current is used to measure theglucose concentration (glucose response value) in the blood.

In the present invention, the blood cells mean red blood cells, whiteblood cells, platelets, and their combinations contained in blood, andpreferably mean red blood cells. In the present invention, the bloodcell amount means, e.g., the ratio (volume ratio) of red blood cells inblood, and preferably means a hematocrit (Hct) value.

Next, the configuration of the measuring device 6 will be described.

The measuring device 6 measures the glucose concentration (bloodcomponent amount) with the biosensor 1 in which blood is introduced, anda blood component contained in the blood is oxidized and reduced by theoxidoreductase. As shown in FIG. 4, when the biosensor 1 is insertedinto the measuring device 6, the measuring device 6 is connected to theelectrodes A to E provided in the end portion 27 of the biosensor 1. Theelectrode A corresponds to the glucose working electrode 21, theelectrode B corresponds to the glucose counter electrode 22, theelectrode C corresponds to the blood cell amount working electrode 23,the electrode D corresponds to the blood cell amount counter electrode24, and the electrode E corresponds to the detecting electrode 26.

The measuring device 6 includes a plurality of connectors 61 to 65, aplurality of switches 66 to 69, a current/voltage converter 70, an A/Dconverter 71, a CPU 72, an LCD 73, and a data storage unit 74 (storagemeans). Moreover, the measuring device 6 includes temperaturemeasurement units 81, 82 for measuring the temperature in the device andswitches 83, 84 for the temperature measurement units 81, 82. Theconnectors 62, 64 and the switches 67, 68 are connected to the glucosecounter electrode 22 (negative electrode) and the blood cell amountcounter electrode 24 (negative electrode), respectively, and aregrounded.

Each of the temperature measurement units 81, 82 measures thetemperature in the measuring device 6 as an ambient temperature of bloodintroduced. For example, it is desirable that the temperaturemeasurement units 81, 82 measure the temperature in the position closerto the biosensor 1 inserted into the measuring device 6. The temperaturevalues measured by the temperature measurement units 81, 82 are suppliedto the CPU 72. The CPU 72 compares the two measured temperature values.If a difference between the temperature values is not within apredetermined threshold value, the CPU 72 determines that either thetemperature measurement unit 81 or 82 has broken down. This makes iteasy and accurate to detect a failure of the measuring device 6.Moreover, this can avoid a measurement error due to an irregulartemperature measurement. The timing of the temperature measurement maybe the time immediately after the introduction of blood is detected bythe detecting electrode 26, or the time when the temperature of bloodintroduced into the biosensor 1 becomes stable.

The connectors 61 to 65 are connected to the electrodes A to E of thebiosensor 1, respectively. The switches 66 to 69 are connected to theconnectors 62 to 65, respectively. The ON and OFF states of the switches66 to 69 are controlled by the CPU 72. To measure the glucoseconcentration, the switch 66 is turned on so that a voltage is appliedbetween the electrode A connected to the glucose working electrode 21and the electrode B connected to the glucose counter electrode 22. Tomeasure the blood cell amount, the switches 67, 68 are turned on so thata voltage is applied between the electrode C connected to the blood cellamount working electrode 23 and the electrode D connected to the bloodcell amount counter electrode 24. Both the voltage applied between theglucose working electrode 21 and the glucose counter electrode 22 andthe voltage applied between the blood cell amount working electrode 23and the blood cell amount counter electrode 24 can be changed. To detectthe introduction of blood, the switch 69 is turned on so that a voltageis applied to the electrode E connected to the detecting electrode 26.

The current/voltage converter 70 is connected to the connectors 61 to 65and the temperature measurement units 81, 82. The current flowingbetween the glucose working electrode 21, the blood cell amount workingelectrode 23, and the other electrodes is supplied to thecurrent/voltage converter 70. Moreover, the current corresponding to theambient temperature measured by the temperature measurement units 81, 82is supplied to the current/voltage converter 70. The current/voltageconverter 70 converts the supplied current into a voltage. Then, thevoltage value is supplied to the A/D converter 71.

The voltage value from the current/voltage converter 70 is supplied tothe A/D converter 71. The A/D converter 71 converts the supplied voltagevalue into digital data in the form of pulses, and outputs the digitaldata to the CPU 72.

The CPU 72 controls each of the units included in the measuring device6. The CPU 72 performs on-off control of the switches 66 to 69.Moreover, the CPU 72 calculates a glucose response value and a bloodcell amount response value of blood based on the digital data from theA/D converter 71. The CPU 72 converts the calculated glucose responsevalue and the calculated blood cell amount response value into a glucoseconversion value and a blood cell amount conversion value. In this case,the CPU 72 converts the calculated glucose response value and thecalculated blood cell amount response value based on a glucose responsevalue and a blood cell amount response value of blood whose glucoseconcentration and blood cell amount have been known. The process ofconverting the glucose response value and the blood cell amount responsevalue into the glucose conversion value and the blood cell amountconversion value will be described later.

The LCD 73 is an LCD (liquid crystal display: output unit) fordisplaying the measured values calculated by the CPU 72.

The data storage unit 74 stores data that can be referred to by the CPU72. The data storage unit 74 stores record data, with which the CPU 72corrects the glucose conversion value. The record data may includeglucose conversion values (blood component amounts) and blood cell valueconversion values that are converted from the respective currentsmeasured more than once within a predetermined period for each bloodwith a known glucose concentration (blood component amount) and a knownblood cell amount. Moreover, the record data may include glucoseconversion values and blood cell value conversion values that aremeasured more than once within the predetermined period for each bloodwith a known glucose concentration and a known blood cell amount and foreach ambient temperature. Further, the record data may include anycombinations of glucose conversion values and blood cell valueconversion values that are measured more than once for each blood with aknown glucose concentration and a known blood cell amount. Further, therecord data may include any combinations of glucose conversion valuesand blood cell value conversion values that are measured more than oncefor each blood with a known glucose concentration and a known blood cellamount and for each ambient temperature.

Next, a basic operation of the measuring device 6 will be described.

When the measuring device 6 measures the glucose concentration and theblood cell amount, first, the introduction of blood is detected by thedetecting electrode 26.

In the measuring device 6, to measure the glucose concentration, the CPU72 turns the switch 66 on so that a voltage (first voltage) is appliedbetween the glucose working electrode 21 and the glucose counterelectrode 22 (first electrode pair). In this state, the CPU 72 detectsan oxidation-reduction current (glucose response value) generated byoxidation-reduction, and converts the oxidation-reduction current into aglucose conversion value (blood component amount measurement means). Theconversion process of the glucose response value will be describedlater.

In the measuring device 6, to measure the blood cell amount, the CPU 72turns the switches 67, 68 on so that a voltage (second voltage) isapplied between the blood cell amount working electrode 23 and the bloodcell amount counter electrode 24 (second electrode pair). In this state,the CPU 72 detects a current (blood cell value response value) generatedby the application of the voltage to the blood cell amount workingelectrode 23 and the blood cell amount counter electrode 24, andconverts the detected current into a blood cell value conversion valuecontained in the blood (blood cell amount measurement means).

The CPU 72 measures the glucose response value and the blood cell valueresponse value within a predetermined period after the introduction ofthe blood into the biosensor 1. The predetermined period can be set to,e.g., 5 seconds or 7 seconds. The CPU 72 controls the measurement insuch a manner that the glucose response value is measured more than onceand the blood cell amount response value is measured more than oncewithin the predetermined period (measurement control means). Therefore,the CPU 72 may perform on-off control of the switches 66 to 68 accordingto the timing of the measurement. The CPU 72 may also control the timingof the acquisition of digital data by the A/D converter 71.

The CPU 72 corrects the measured glucose conversion value based on atleast a part of a plurality of glucose conversion values and a pluralityof blood cell value conversion values (blood component amount correctionmeans). The glucose conversion value (blood component amount) to becorrected is, e.g., a glucose conversion value measured at the end ofthe predetermined period. The glucose conversion value to be correctedmay be any value measured during the predetermined period rather thanthe value measured at the end of the predetermined period. In this case,the CPU 72 refers to the record data. As the blood component amountcorrection means, the CPU 72 compares the record data including aplurality of glucose conversion values and a plurality of blood cellvalue conversion values stored in the data storage unit 74 with themeasured data including a plurality of glucose conversion values and aplurality of blood cell value conversion values. The CPU 72 corrects anyglucose conversion value measured during the predetermined period to theglucose concentration of blood having the record data that is mostclosely approximated to the measured data.

In the measuring device 6, when the data storage unit 74 stores therecord data including a plurality of glucose conversion values and aplurality of blood cell value conversion values for each ambienttemperature, the ambient temperature may be measured by the temperaturemeasurement units 81, 82 and the record data with the measured ambienttemperature may be used. The measuring device 6 compares the record dataincluding a plurality of glucose conversion values and a plurality ofblood cell value conversion values corresponding to the measured ambienttemperature with the measured data including a plurality of glucoseconversion values and a plurality of blood cell value conversion values.Thus, the measuring device 6 can correct the glucose conversion value ofthe measured data to the glucose concentration of blood having therecord data that is most closely approximated to the measured data.

In the measuring device 6, when the data storage unit 74 stores therecord data including any combinations of glucose conversion values andblood cell value conversion values, the measured data including the samecombinations of glucose conversion values and blood cell valueconversion values as those of the record data may be used. The measuringdevice 6 compares the record data including any combinations of theglucose conversion values and the blood cell value conversion valueswith the measured data including the same combinations of the glucoseconversion values and the blood cell value conversion values as those ofthe record data. Thus, the measuring device 6 can correct the glucoseconversion value of the measured data to the glucose concentration ofblood having the record data that is most closely approximated to themeasured data.

Next, an operation of the measuring device 6 to convert the glucoseresponse value and the blood cell amount response value into the glucoseconversion value and the blood cell amount conversion value will bedescribed.

In the measuring device 6, the glucose concentration is supplied to theCPU 72 as a glucose response value that is a current value, a voltagevalue, and digital data that are proportional to the glucoseconcentration. The glucose response value that is expected to besupplied to the CPU 72 is shown in, e.g., FIG. 5. For example, when theglucose concentration is 100 mg/dl and the blood cell amount (Hct) is25%, the CPU 72 is expected to receive a glucose response value (currentvalue) of 120 and a blood cell value response value (current value) of1250. Such predicted values of the glucose response value and the bloodcell amount response value can be obtained by preparing blood in whichthe glucose concentration and the blood cell amount have previously beenadjusted, and measuring the blood with the biosensor 1 and the measuringdevice 6.

The glucose response values and the blood cell amount response valuesshown in FIG. 5, which are obtained from blood with a known glucoseconcentration and a known blood cell amount, are plotted on a graph, andthen the points plotted on the graph are joined to form lines, resultingin a glucose concentration conversion matrix as shown in FIG. 6. Theglucose concentration conversion matrix shows that the glucose responsevalue of blood varies with different blood cell amounts even if theglucose concentration is the same.

In the glucose concentration conversion matrix, any glucose responsevalue plotted on the line containing the points derived from the sameknown glucose concentration can be converted into the known glucoseconcentration. Therefore, by using the glucose concentration conversionmatrix, the glucose conversion value can be obtained from the glucoseresponse value and the blood cell amount response value of unknownblood. For example, when the glucose response value and the blood cellamount response value are given as indicated by a white circle in FIG.6, the ratio (A B) of the glucose response value at 100 mg/dl to theglucose response value at 200 mg/dl in the glucose concentrationconversion matrix is determined, and thus the glucose conversion valueof 138 mg/dl can be obtained.

Similarly, in the glucose concentration conversion matrix, any bloodcell amount response value plotted on the line containing the pointsderived from the same known blood cell amount can be converted into theknown blood cell amount. Therefore, by using the glucose concentrationconversion matrix, the blood cell amount response value can be obtainedfrom the glucose response value and the blood cell amount response valueof unknown blood.

As described above, the use of the glucose concentration conversionmatrix can provide the glucose conversion value and the blood cellamount conversion value from the glucose response value and the bloodcell amount response value.

Next, an operation of the measuring device 6 to correct the glucoseconversion value of the measured data by comparing the record data withthe measured data will be described.

The measuring device 6 of this embodiment obtains a plurality of glucoseresponse values and a plurality of blood cell amount response values bythe operations described with reference to, e.g., FIGS. 7 and 8.Moreover, the measuring device 6 refers to the glucose concentrationconversion matrices shown in FIGS. 9 to 12 and can convert the glucoseresponse values and the blood cell amount response values into glucoseconversion values and blood cell amount conversion values.

To measure the glucose concentration, the measuring device 6 applies afirst voltage shown in FIG. 7A between the glucose working electrode 21and the glucose counter electrode 22. For example, the CPU 72 applies afirst voltage of 350 mV between the glucose working electrode 21 and theglucose counter electrode 22. As shown in FIG. 7A, the first voltage iscontinuously applied over a predetermined period in which the glucoseconcentration is being measured. Alternatively, the first voltage may beintermittently applied only at the predetermined timing of themeasurement of the glucose response value, instead of the continuousapplication. The predetermined period may be, e.g., 0 to 7 seconds.

To measure the blood cell amount, the measuring device 6 applies asecond voltage shown in FIG. 7B between the blood cell amount workingelectrode 23 and the blood cell amount counter electrode 24. Forexample, the CPU 72 applies a second voltage of 2500 mV between theblood cell amount working electrode 23 and the blood cell amount counterelectrode 24. However, the second voltage is not limited thereto as longas the blood cell amount can be measured. As shown in FIG. 7B, thesecond voltage is applied at least twice, i.e., in the first half andthe second half of the predetermined period.

The CPU 72 applies both the first voltage and the second voltage shownin FIGS. 7A and 7B to the biosensor 1, and then acquires the glucoseresponse values and the blood cell amount response values at timingshown in FIG. 8. The CPU 72 acquires the glucose response value twice,i.e., in a first period included in the first half of the predeterminedperiod and in a second period included in the second half of thepredetermined period. Consequently, the CPU 72 can acquire a glucoseresponse value G1 and a glucose response value G2. Moreover, the CPU 72acquires the blood cell amount response value twice, i.e., in the firstperiod included in the first half of the predetermined period and in thesecond period included in the second half of the predetermined period.Consequently, the CPU 72 can acquire a blood cell amount response valueH1 and a blood cell amount response value H2.

It is desirable that the first period is set during which a change intemperature of the blood introduced into the biosensor 1 is large.Alternatively, it is preferable that the end point of the first periodis set to the time at which a blood temperature difference is large whenthe biosensor 1 finishes the measurement. For example, the first periodmay be within a short period from the start of the measurement by thebiosensor 1. In the example of FIG. 8, the first period may be within1.5 seconds from the start of the measurement. It is desirable that thesecond period is set during which a change in temperature of the bloodintroduced into the biosensor 1 is stable. Alternatively, it ispreferable that the start point of the second period is set to the timeat which a blood temperature difference is small when the biosensor 1finishes the measurement. For example, the second period may be within ashort period from the end of the measurement by the biosensor 1. In theexample of FIG. 8, the second period may be after 6 to 7 seconds fromthe measurement.

As described above, the measuring device 6 applies the first voltage tothe first electrode pair of the glucose working electrode 21 and theglucose counter electrode 22 in the predetermined period, and detects anoxidation-reduction current corresponding to the blood component amountmore than once at the predetermined timing of the measurement of theblood component amount. On the other hand, the measuring device 6applies the second voltage within a predetermined short time before,during, or after the predetermined timing of the measurement of theblood component amount. Further, the measuring device 6 applies thesecond voltage in pulses to the second electrode pair of the blood cellamount working electrode 23 and the blood cell amount counter electrode24 only at the timing of the measurement of the blood cell amount in thepredetermined period, and detects a current corresponding to the bloodcell amount.

When the two glucose response values G1, G2 and the two blood cellamount response values H1, H2 are measured, the CPU 72 refers to fourglucose concentration conversion matrices and calculates the glucoseconversion values and the blood cell amount conversion values. In thiscase, the four glucose concentration conversion matrices are preparedfor each of the following combinations: the combination of the glucoseresponse value G1 and the blood cell amount response value H1; thecombination of the glucose response value G2 and the blood cell amountresponse value H1; the combination of the glucose response value G2 andthe blood cell amount response value H1; and the combination of theglucose response value G2 and the blood cell amount response value H2.

The CPU 72 uses the glucose concentration conversion matrix G1-H1 inFIG. 9 to convert the glucose response value G1 and the blood cellamount response value H1 of the measured data into a glucose conversionvalue and a blood cell amount conversion value. Similarly, the CPU 72uses the glucose concentration conversion matrix G1-H2 in FIG. 10 toconvert the glucose response value G1 and the blood cell amount responsevalue H2 of the measured data into a glucose conversion value and ablood cell amount conversion value. Similarly, the CPU 72 uses theglucose concentration conversion matrix G2-H1 in FIG. 11 to covert theglucose response value G2 and the blood cell amount response value H1 ofthe measured data into a glucose conversion value and a blood cellamount conversion value. Similarly, the CPU 72 uses the glucoseconcentration conversion matrix G2-H2 in FIG. 12 to convert the glucoseresponse value G2 and the blood cell amount response value H2 of themeasured data into a glucose conversion value and a blood cell amountconversion value.

Specifically, in the measuring device 6, the data storage unit 74 storesthe glucose concentration conversion matrices shown in FIGS. 9 to 12.The measuring device 6 measures the glucose response values and theblood cell amount response values of unknown blood, and acquires themeasured data including a group of G1 and H1, a group of G1 and H2, agroup of G2 and H1, and a group of G2 and H2. Then, the measuring device6 plots the point determined by the combination of the glucose responsevalue and the blood cell amount response value of the measured data onthe corresponding glucose concentration conversion matrix, and convertsthe glucose response value and the blood cell amount response value intoa glucose conversion value and a blood cell amount conversion value.Consequently, the measuring device 6 can obtain the glucose conversionvalue and the blood cell amount conversion value from each of the groupof G1 and H1, the group of G1 and H2, the group of G2 and H1, and thegroup of G2 and H2.

Next, the measuring device 6 compares a plurality of groups of theglucose conversion values and the blood cell amount conversion values ofthe record data with a plurality of groups of the glucose conversionvalues and the blood cell amount conversion values of the measured data.As a result of the comparison, the measuring device 6 can correct theglucose conversion value of the measured data to the glucose conversionvalue of the record data that is closest to the measured data.

As shown in FIG. 13, the temperature of blood (sample) introduced intothe biosensor 1 decreases with elapsed time after the introduction ofthe blood into the biosensor 1. As described above, when the measurementtime (predetermined time) of the glucose concentration is 7 seconds,such a decrease in temperature of the blood over the measurement timediffers depending on the blood temperature at the time of theintroduction of the blood into the biosensor 1. The slope of a decreasein temperature of the blood increases with increasing the bloodtemperature at the time of the introduction of the blood into thebiosensor 1. Moreover, the blood temperature at the end of themeasurement time differs depending on the blood temperature at the timeof the introduction of the blood into the biosensor 1. A differencebetween the blood temperature and the ambient temperature at the end ofthe measurement time increases as the blood temperature becomes higherwhen the blood is introduced into the biosensor 1. For example, whenblood of 30° C. is introduced into the biosensor 1, a difference betweenthe blood temperature and the ambient temperature at the end of themeasurement time is T1. When blood of 25° C. is introduced into thebiosensor 1, a difference between the blood temperature and the ambienttemperature at the end of the measurement time is T2. When blood of 20°C. is introduced into the biosensor 1, a difference between the bloodtemperature and the ambient temperature at the end of the measurementtime is T3.

Since the glucose response value and the blood cell amount responsevalue measured by the measuring device 6 depend on the bloodtemperature, if the glucose response value and the blood cell amountresponse value are measured only at the end of the measurement time, itis not possible to obtain an accurate glucose response value and anaccurate blood cell amount response value. Therefore, the measuringdevice 6 measures the glucose response value and the blood cell amountresponse value more than once in the measurement time, and obtains theglucose conversion values and the blood cell amount conversion values.Moreover, the measuring device 6 combines the glucose response valuesand the blood cell amount response values as desired, and obtains thedesired combinations of the glucose conversion values and the blood cellamount conversion values.

In the measuring device 6, the data storage unit 74 stores the recorddata shown in, e.g., FIG. 14. This record data may be prepared in thefollowing manner. For example, using blood with a glucose concentrationof 100 mg/dl and a blood cell amount of 25%, the glucose response valuesand the blood cell amount response values are measured at each ambienttemperature as well as at each sample introduction temperature. Then,the glucose conversion values are obtained for each of the abovecombinations. The sample introduction temperature does not need to beincluded in the record data. Specifically, in the record data, theambient temperature A is associated with a glucose conversion value Aa1obtained from the glucose concentration conversion matrix G1-H1 in FIG.9, a glucose conversion value Aa2 obtained from the glucoseconcentration conversion matrix G1-H2 in FIG. 10, a glucose conversionvalue Aa3 obtained from the glucose concentration conversion matrixG2-H1 in FIG. 11, and a glucose conversion value Aa4 obtained from theglucose concentration conversion matrix G2-H2 in FIG. 12. It isdesirable that the record data includes the glucose conversion values ata plurality of sample introduction temperatures for each ambienttemperature. Moreover, it is desirable that the record data includes theglucose conversion values at each of a plurality of ambienttemperatures.

The measuring device 6 can compare the glucose conversion values foreach of the combinations of the glucose response values and the bloodcell amount response values of the measured data with the glucoseconversion values of the record data, and thus can determine the mostapproximate record data. Specifically, when the ambient temperature isabout A, the measuring device 6 extracts the glucose conversion valuesAa1 to Aa4, Ab1 to Ab4, and Ac1 to Ac4 for each of the combinationscorresponding to the ambient temperature A. The measuring device 6compares the glucose conversion values for each of the combinations ofthe measured data with the extracted glucose conversion values Aa1 toAa4, Ab1 to Ab4, and Ac1 to Ac4. If the glucose conversion values foreach of the combinations of the measured data are closely approximatedto the glucose conversion values Aa1 to Aa4, Ab1 to Ab4, and Ac1 to Ac4,then the measuring device 6 can correct the glucose conversion value ofthe measured data to 100 mg/dl.

As described above, the measuring device 6 converts the measured glucoseresponse values and the measured blood cell amount response values intoa plurality of glucose conversion values and a plurality of blood cellamount conversion values. Based on the glucose conversion values and theblood cell amount conversion values, the measuring device 6 can correctthe glucose conversion value of the measured data. Thus, this biosensorsystem can suppress the measurement error of the glucose concentrationcompared to the use of the current value generated by theoxidation-reduction reaction.

The glucose conversion values of the measured data differ depending onthe ambient temperature of the biosensor 1. For example, assuming thatthe glucose concentration conversion matrices in FIGS. 9 to 12 areprepared at an environmental temperature of 25° C., blood with a glucoseconcentration of 125 mg/dl is measured at an ambient temperature of 25°C. in the biosensor 1, and the glucose conversion values are calculatedfrom the glucose response values G1, G2 and the blood cell amountresponse values H1, H2. As shown in FIG. 15, the resultant glucoseconversion values of all the combinations are 125 mg/dl. However, if theambient temperature of the biosensor 1 is changed to 35° C., the glucoseconversion values of all the combinations are different.

When the blood cell amount is changed, the glucose conversion values ofthe measured data can vary by the degree of the influence shown in,e.g., FIG. 16. If the blood cell amount is changed by 25%, the glucoseconversion values vary by 20% with a glucose concentration of 100 mg/dl.Moreover, the glucose conversion values vary by 25% with a glucoseconcentration of 200 mg/dl, and the glucose conversion values vary by21% with a glucose concentration of 110 mg/dl.

When the ambient temperature of the biosensor 1 is changed, as shown inFIG. 17, even if blood has a known glucose concentration of 100 mg/dland a known blood cell amount response value of 1000 mV, both theglucose response value and the blood cell amount response value measuredcan vary due to the degree of the influence of temperature.

As described above, the glucose conversion values differ depending onthe ambient temperature. Moreover, the glucose response values vary withthe ambient temperature and the blood cell amount. Therefore, even ifblood with the same glucose concentration is measured to calculate theglucose response values and the blood cell amount response values, theglucose conversion values differ depending on the cases A, B to bemeasured, as shown in FIG. 18. In the case A, the glucose conversionvalue is 103 mg/dl. In the case B, the glucose conversion value is 110mg/dl.

Thus, in the measuring device 6, it is desirable that the data storageunit 74 stores the record data at each ambient temperature in view ofthe influence of the ambient temperature on the glucose response valuesand the blood cell amount response values. The measuring device 6extracts the record data closer to the current ambient temperature fromthe record data stored in the data storage unit 74. The measuring device6 compares the glucose conversion values included in the record datathat has been extracted in accordance with the current ambienttemperature with the glucose conversion values of the measured data.Thus, the measuring device 6 can correct the glucose conversion value ofthe measured data to the glucose conversion value of the mostapproximate record data.

As described above, the blood temperature in the biosensor 1 is changedfrom the time of the introduction of the blood to the end of themeasurement, and the glucose response value varies with the blood cellamount. Therefore, as described above, it is desirable that themeasuring device 6 makes any combinations of a plurality of glucoseresponse values and a plurality of blood cell amount response valuesmeasured during the predetermined measurement time, and then calculatesthe glucose conversion values. Thus, even if the blood temperature ischanged and the blood cell amount is unknown, as described above, themeasuring device 6 can calculate the glucose conversion values from anycombinations of the glucose response values and the blood cell amountresponse values, and can select the record data that is closelyapproximated to the glucose conversion value of the measured data.

Specifically, the measuring device 6 measures the glucose response valueand the blood cell amount response value in the first period included inthe first half of the predetermined period and in the second periodincluded in the second half of the predetermined period. Therefore, themeasuring device 6 can acquire the glucose response value and the bloodcell amount response value both when a change in temperature is largeand when a change in temperature is stable. Thus, even if the bloodtemperature is changed differently every time the measurement isperformed, the measuring device 6 can obtain the glucose conversionvalues and the blood cell amount conversion values of the measured datain a plurality of periods, and can correct them with the record data.This can reduce the disadvantage that the glucose conversion values varywith blood temperature changes so that accurate glucose conversionvalues cannot be obtained.

It is desirable that the measuring device 6 performs the measurement asmany as possible during the predetermined period in order to improve thecorrection accuracy of the measured data. For example, the first voltageis applied to the biosensor 1 to measure the glucose response values, asshown in FIG. 19A, and the second voltage is applied to the biosensor 1to measure the blood cell amount response values, as shown in FIG. 19B.The measuring device 6 acquires the blood cell amount response valuesand the glucose response values at the measurement points shown in FIG.20. Thus, the measuring device 6 can obtain 9 glucose response valuesand 9 blood cell amount response values within the predetermined period.

The measuring device 6 combines the 9 glucose response values and the 9blood cell amount response values to make 81 groups of the glucoseresponse values and the blood cell amount response values. In otherwords, the measuring device 6 combines the glucose response values G1 toG9 with the blood cell amount response values H1 to H9. Therefore, themeasuring device 6 can obtain a glucose conversion value from G1-H1, . .. , and a glucose conversion value from G1-H9, as shown in FIG. 21.Similarly, the measuring device 6 can obtain a plurality of glucoseconversion values from the combinations of G2 and H1 to H9, . . . , anda plurality of glucose conversion values from the combinations of G9 andH1 to H9. Thus, the measuring device 6 compares 81 glucose conversionvalues of the measured data with 81 glucose conversion values of therecord data, and can select the record data that is most closelyapproximated to the measured data. Accordingly, the measuring device 6can correct the glucose conversion value of the measured data to theglucose conversion value of the record data obtained using the 81glucose conversion values.

As described above, the record data is prepared to include manycombinations of the glucose conversion values and the blood cell amountconversion values, and the same combinations of the glucose conversionvalues and the blood cell amount conversion values of the measured dataas those of the record data can be used to correct the measured data.Therefore, even if the glucose conversion values vary with bloodtemperature changes, the ambient temperature, and the blood cell amount,as described above, since many combinations of the glucose conversionvalues and the blood cell amount conversion values are used, themeasured data can be corrected to the glucose conversion value with lesserror.

Next, another embodiment that differs from the above embodiment will bedescribed.

A measuring device 6 of this embodiment performs a multivariate analysiswith the use of at least a part of the measured glucose conversionvalues and the measured blood cell amount conversion values, and thencorrects the glucose repose values measured within a predeterminedperiod. This measuring device 6 differs from the measuring device 6 ofthe above embodiment in that the data storage unit 74 is not provided,as shown in FIG. 22.

Similarly to the above embodiment, the measuring device 6 measures aplurality of glucose response values and a plurality of blood cellamount response values. The CPU 72 performs the multivariate analysis byusing a part or the whole of the measured glucose response values andthe measured blood cell amount response values, and obtains the finalglucose conversion value. The measuring device 6 may perform, e.g., amultiple regression analysis as the multivariate analysis. The multipleregression analysis uses as a response function, e.g., the followingmultiple regression equation of a linear polynomial:Glucose conversion value=a×G1+b×H1+c×G2+ . . . +n×Gn+(n+1)×Hn+Co,where Co represents a constant, a, b, c, . . . , n representcoefficients by which the glucose response values are multiplied, Gnrepresents a glucose response value, and Hn represents a blood cellamount response value. In this multiple regression analysis, a knownglucose concentration is used as a target value, and the process ofdetermining the coefficients of the multiple regression equation isperformed. The CPU 72 determines the coefficients (a, b, c, . . . , n)of the multiple regression equation, by which one or more glucoseresponse values are multiplied, based on the results of the measurementof the glucose response values G1 to G9 in combination with the bloodcell amount response values H1 to H9 at different ambient temperaturesand different sample introduction temperatures under the conditions thatthe ambient temperature and the sample introduction temperature arevariously controlled. This can provide the response function that servesas a correction factor for the influence of temperature during themeasurement and incorporates the ambient temperature and the sampleintroduction temperature. Thus, the CPU 72 performs the regressionanalysis to determine a correction formula that corrects the differencebetween an intermediate conversion value and the known value to zero.The intermediate conversion value is obtained using each of the glucoseresponse values and the blood cell amount response values.

As described above, the measuring device 6 of this embodiment convertsthe glucose response values and the blood cell amount response valuesinto the glucose conversion values and the blood cell amount conversionvalues, and then can determine the final glucose concentration by theoperation (correction operation) of the multiple regression analysis.Thus, the measuring device 6 can suppress the measurement error of theglucose concentration, compared to the case where the glucose responsevalues themselves are used to obtain the glucose concentration.

The value determined by the multiple regression analysis is not limitedto the glucose conversion value and may be, e.g., the amount ofcorrection of the glucose conversion value.

The multiple regression analysis may also use as a response function,e.g., the following multiple regression equation of a quadraticpolynomial.

$\begin{matrix}{{{Glucose}\mspace{14mu}{conversion}\mspace{14mu}{value}} = {\beta_{0} + {\sum\limits_{i = 1}^{k}{\beta_{i}x_{i}}} + {\sum\limits_{i = 1}^{k}{\beta_{ii}x_{i}^{2}}} + {\sum\limits_{i < j}{\beta_{ij}x_{i}x_{j}}}}} & \left\lbrack {{Formula}\mspace{14mu} 1} \right\rbrack\end{matrix}$

In the quadratic polynomial, any combination of the glucose responsevalues (G1 to Gm, where m represents the number of numerical values tobe measured) and the blood cell response values (H1 to Hp, where prepresents the number of numerical values to be measured) can beassigned to each of the variables xi. Like the linear polynomial, thecoefficients of the quadratic polynomial are determined by the learningprocess.

In the quadratic polynomial, when a total of 18 groups of the glucoseresponse values and the blood cell response values are selected to forma glucose concentration conversion formula or a correction formula, thenumber of terms of the correction formula is 190 (including a constantterm).

In determining the coefficients actually, higher-order terms (xi², xixj,etc.) may be reduced to first-order terms containing parameters by achange of variables. Therefore, the actual calculation to determine thecoefficients becomes the same as that in the linear polynomial. Thevariables of the quadratic polynomial may include the ambienttemperature measured by the measuring device 6 in addition to theglucose response values and the blood cell response values.

When the glucose concentration conversion formula or the correctionformula is expressed as a quadratic polynomial, it is likely to reducethe error in the actual distribution of the terms compared to the linearpolynomial.

The above quadratic polynomial is equal to an approximate functionobtained by the Taylor expansion of a hypersurface up to second order.The hypersurface defines a distribution in a multidimensional spaceusing the variables (e.g., the glucose response values and the bloodcell response values incorporated into the correction formula) as axes.As long as it is theoretically confirmed that the estimated distributionis continuous, if regions of the variables (the selected group ofglucose response values and the selected group of blood cell responsevalues) are sufficiently narrow, high accuracy can be achieved inprinciple. Although higher-order variables may be used, when theresponse values with the same quantity are combined, the number of termsof the glucose conversion formula or the correction formula isincreased. This leads to the disadvantages of making the computationmore complicated, and increasing the minimum number of data required todetermine the coefficients.

The above example uses the linear regression equation as a form of theglucose conversion formula or the correction formula. However, theregression equation does not necessarily need to be linear. For example,the variables xi (including the glucose response values, the blood cellresponse values, and the ambient temperature) may be combined withoperators to form terms, and the terms may be linearly added. In thiscase, when the regression analysis is performed to determine thecoefficients of the terms, each of the terms is reduced to a linearequation with parameters by a change of variables, as in the case of thelinear polynomial and the quadratic polynomial. Thus, the technique ofthe multiple regression analysis of the linear polynomial can be appliedto the present invention.

The above embodiments are merely an example of the present invention.Therefore, the present invention is not limited to the aboveembodiments, and it is to be understood that various modifications maybe introduced in accordance with the design or the like into anyembodiment other than the above without departing from the technicalidea of the present invention.

DESCRIPTION OF REFERENCE NUMERALS

-   -   1 Biosensor    -   2 Blood component measurement layer    -   6 Measuring device    -   21 Glucose working electrode (first electrode pair, blood        component amount measuring pair)    -   22 Glucose counter electrode (first electrode pair, blood        component amount measuring electrode pair)    -   23 Blood cell amount working electrode (second electrode pair,        blood cell amount measuring electrode pair)    -   24 Blood cell amount counter electrode (second electrode pair,        blood cell amount measuring electrode pair)    -   25 Non-interacting portion    -   26 Detecting electrode    -   72 CPU (blood component amount measurement means, blood cell        amount measurement means, measurement control means, blood        component amount correction means)    -   74 Data storage unit (storage means)    -   81, 82 Temperature measurement unit

The invention claimed is:
 1. A method for measuring a blood componentthat measures a blood component amount with a biosensor in which bloodis introduced, and a blood component contained in the blood is oxidizedand reduced by an oxidoreductase, the method comprising: measuring afirst current value generated when a first voltage is applied to a firstelectrode pair of the biosensor, measuring multiple times a secondcurrent value generated when a second voltage is applied to a secondelectrode pair of the biosensor multiple times, and correcting themeasured first current value based on at least a part of the measuredfirst and second current values, wherein measuring the first currentvalue is conducted by applying the first voltage to the first electrodepair during a predetermined period after introduction of the blood tothe biosensor, and detecting the current at the predetermined timing fordetection of the first current, measuring the second current valuemultiple times is conducted by applying a pulse of the second voltage tothe second electrode pair during a predetermined short period from themeasuring of the second current and during a predetermined timing fordetection of the second current, and detecting the current correspondingto each of the second currents.
 2. The method for measuring a bloodcomponent according to claim 1, wherein the second voltage is applied tothe second electrode pair only at the timing of the measurement of thesecond current value in the predetermined period while the first voltageis being applied to the first electrode pair.